Parkinson's disease (P-D) is a common neurodegenerative disorder characterized by bradykinesia, rigidity and tremor; current treatments neither slow progression nor adequately control the most disabling symptoms. Most of PD's clinical features result from the loss of dopamine (DA) neurons in the substantia nigra pars compacta (Snpc). Thus far, the cause and pathogenesis of PD are unknown. This knowledge is critical to learn how to prevent PD's inexorable progression. The unifying theme of this PD Center relates to neurodegeneration in PD; our goal is to unravel its pathogenesis in lab projects 1-4 and quantify its progression in clinical projects 5&6. Project 1 investigates two animal models of PD, i.e., loss of Snpc neurons in the MPTP mouse and in the transgenic mouse expressing mutant Cu/Zn superoxide dismutase (Msod1). We explore our observation that MPTP stimulates the production of hypochlorous acid, a highly reactive tissue damaging species. Through a series of DNA strand breakage and poly (ADP-ribose) polymerase (PARP) activation in the MPTP model. It will also explore the increased cytosolic DA pool leads to degeneration of Snpc neurons and produces cytoplasmic ubiquitinated inclusions reminiscent of Lewy bodies, a hallmark of PD. Project 2 investigates how altering intracellular DA in cultures of SN neurons from genetically engineered mice triggers molecular mechanisms to initiate degeneration of DA neurons. Project 3 evaluates the hypothesis that abnormally re-activated programmed cell death (PCD) (which occurs normally during development) plays a role in pathogenesis of PD. Project 3 examines the role of the signaling molecule c-jun, its kinase, JNK, the death effector caspase-3, and a tau and neurofilament kinase cdk5 in paradigms of PCD in dopaminergic Snpc neurons. Project 4 will identify genes that play roles in the 6-OHDA-induced degeneration of monoaminergic PC12 cells utilizing a new technique, Serial Analysis of Gene Expression (SAGE) and then will determine the expression of such genes in animal models and in POD brains. TO develop a biologic marker to quantify DA neurodegeneration in humans, Project 5 will correlate longitudinal clinical evaluations and positron emission tomography (PET)-generated metabolic findings in a cohort of early PD patients. Development of a biomarker is necessary to assess disease progression in future clinical trials testing potential neuroprotective therapies. Project 6 is an epidemiological study designed to explain the lower prevalence rates of PD in Blacks and women; it will evaluate, among other hypotheses, the possibility that biological differences may affect rates of progression.